AbdelAziz Y. Elzouki, Khalid Mirza, Ayman Mahmood, Abdul Mohsen Al-Sowailem 113

Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. There are two main subgroups: the typical form of HUS follows a diarrheal prodrome (D+HUS) and the atypical form is without the diarrheal prodrome (D-HUS). We have studied 28 children with HUS over a period of 15 months between 1992and 1993. The median age was 2.2 years (range from six months to six years). All children had prodromal diarrhea. Hypertension was present in 71% and neurological complications in 39%. All the patients had oliguria or anuria (16 oliguric and 12 anuric). The mean duration of anuria was 16 days (range seven to 42 days). Serum creatinine on admission ranged between 112 and 1064 µmol/L (mean 453 µmol/L). The lowest hemoglobin level and platelet count during hospitalization ranged between 38 and 87 g/L and 7 to 147x109/L respectively. Leukocytosis on admission was present in 22 patients, low C3 was documented in 11 patients (34%), and four patients had low C4. All patients received fresh frozen plasma transfusion, a total of 25 patients received dialysis therapy, 19 patients were treated with peritoneal dialysis (PD), one patient had hemodialysis (HD), and five patients had both HD and PD. The mean duration of dialysis was 18 days (range three to 56 days). Only one patient died (mortality rate 3%). The median duration of hospital stay was 28 days (range eight to 90 days). We conclude that HUS is emerging as an important clinical and public health problem and that early comprehensive management including dialysis therapy, aggressive management of hypertension, fresh frozen plasma transfusion, and nutritional support all improve the outcome and decrease the mortality and morbidity in patients with HUS.

Hemolytic Uremic Syndrome
Hemolytic uremic syndrome (HUS) is a predominantly pediatric condition that consists of the simultaneous triad of hemolytic anemia, thrombocytopenia and acute renal failure. Although uncommon, occurring in approximately 100 children in Canada per year, it is the most common cause of acute renal failure in children and is fatal in a small percentage o children (less than 5%).1 The recent E. coli epidemic in Walkerton, Ontario and ongoing concern about coliform contamination of water supplies has resulted in discussion of HUS in the media and has raised awareness of HUS in the general public. Timely diagnosis and optimal management require physicians to be knowledgeable about this syndrome and when to suspect HUS.

HUS - Causative Factors
HUS is commonly divided into two groups; those occurring after a diarrheal illness and non-diarrheal HUS. Diarrhea associated HUS is the most common, comprising 75% of all the cases. The most common causative agent is Escherichia coli 0157:H7. Most E.coli 0157 infections result in mild diarrhea but hemorrhagic colitis can occur. HUS occurs in about 10% of children with E.coli 0157:H7 hemorrhagic colitis.1 Diarrhea associated HUS usually occurs in young children (7 months to 6 years), predominantly in summer and early fall. Sources of contamination include undercooked meat, unpasteurized milk or juice or contaminated water. It can be passed from person to person. Other bacterial diarrheal agents that can cause HUS include Shigella and Salmonellas.

Non-diarrheal HUS is more uncommon and tends to occur in older or very young children and has no seasonal predilection. It can occur after Streptococcus pneumoniae infection, malignancy or certain drugs. Some are inherited in either an autosomal dominant or recessive pattern and these patients often experience relapse, hypertension and chronic renal disease.

Pathogenesis and Pathology
HUS pathology and pathogenesis is very similar to thrombocytopenic purpura (TTP) which occurs mainly in adults. The initiating factor seems to be injury of the glomerular endothelium or, in some cases, an imbalance of platelet aggregation factors. This results in fibrin deposits and platelet clumping within the capillaries. As this process continues, the capillaries occlude resulting in decreased glomerular filtration rate and renal failure. Red blood cells traveling through the plugged capillaries are damaged causing hemolytic anemia. Platelets are used up in the clumping process and are damaged in the blood vessels resulting in decreased platelets. This is a simplistic version of the possible events that occur in the development of HUS.2

On histologic examination in the kidney of patients with HUS, changes in glomeruli vary from minimal to severe with abnormalities such as endothelial edema, degeneration of endothelium, thickening of capillary walls, thrombi and fragmented RBCs. histologic abnormalities may occur in only some glomeruli. In patients with persistent renal abnormalities years after HUS, biopsy may show glomerulosclerosis.3

Clinical Clues to Diagnosis
Most patients present with diarrhea 3-12 days before the onset of HUS. It is important to know that the diarrhea may be resolving when HUS develops. The diarrheal illness may be like viral gastroenteritis and can be watery or bloody. The child may or may not have associated cramping, vomiting or fever. The early signs of HUS may be subtle. Often the child becomes more ill, restless, and irritable. Pallor develops due to the anemia. Petechiae, purpura and oozing may occur. Oliguria is an important indicator but it is often difficult to determine on history if the child is having significant diarrhea. If renal failure is not noted and excess fluids are given, signs of fluid overload such as edema, hypertension and chest congestion can occur. The central nervous system manifestations vary considerable and can include irritability, ataxia, coma or seizures. Gastrointestinal involvement may result in infarction, intussusseption, perforation or hepatomegaly. The clinical clues are important to elicit on history and physical exam as they prompt the appropriate investigations leading to a diagnosis.

Laboratory Investigations
Initial labs should include stool culture, CBC and differential, blood smear, electrolytes, urea, creatinine and urinalysis. In a child who is unwell with gastroenteritis, a CBC, electrolytes, urea and creatinine are often obtained and these alone should provide evidence for HUS. The stool culture is important for identification of the causative organism. E.coli 0157:H7 is the most common organism found and is a reportable infection. This allows public health officials to search for the source and identify possible outbreaks. The CBC initially shows thrombocytopenia and this may be the only abnormality early in the course. Later the platelets are often <40,000, anemia is present and the WBC may be normal or elevated. Reticulocytes are high. A blood smear shows schistocytes, burr cells and helmet cells due to hemolysis. Electrolyte abnormalities include hyponatremia, hyperkalemia and acidosis. The urea and creatinine may be elevated to varying degrees depending upon the severity at presentation. Urinalysis reveals protenuria, RBCs and casts.

Other lab values which may be done include the Coomb's test which is negative, high LDH due to hemolysis, high triglycerides, low complement (C3 and C4), normal PT and PTT and increased fibrinogen degradation products. Liver enzymes may also be slightly elevated and serum protein and albumin may be decreased. These tests are not necessary for diagnosis but some may be ordered to exclude other diagnoses and others, such as TGs may be helpful in caring for patients with HUS.

Clinical Course
The duration of HUS is variable depending on the severity. In mild HUS the urine output may be normal and the renal failure mild, resolving with close observations only. More severe HUS however, can involve days to weeks of anuria and dialysis, transfusion and the possibility of complications. The usual course lasts 1-2 weeks with an initial worsening and then stabilization followed by gradual recovery. Recovery is heralded by a rise in platelets, followed by improving urine output and then resolution of the anemia.

The initial management involves the management of any child with a diarrheal illness where the causative agent is unknown or is found to be E.coli 0157:H7. They should not be treated with antimotility agents as this may result in longer diarrheal course and perhaps an increased risk of HUS although this controversial.4 There is certainly no benefit to antimotility agents. Antibiotics should not be given as it has been recently shown to be associated with an increased risk of HUS.5 If you are awaiting laboratory investigations but suspect HUS it is important to avoid overhydration. In a patient with diarrhea and poor urine output, one often desires to give extra fluids but it is advisable to be cautious with fluids until laboratory values and observation allow diagnosis.

In the near future, a child with diarrheal illness due to R.coli 0157:H7 or suspicious for this bacteria may be treated with an agent that binds the toxin within the bowel to prevent HUS. One such agent, SYSNSORB Pk, has been undergoing testing but is not yet generally available. Immunization strategies are also under investigation.6

Once HUS is diagnosed, the volume status of the child is paramount. If urine output is difficult to measure given the diarrhea, a catheter may be necessary. Consultation with a pediatrician and transfer to a tertiary care center should be done when HUS is diagnosed, since renal failure and other complications may progress rapidly. The patient's weight should be accurately measured and followed closely. Other investigations such as chest X-ray or abdominal films may be necessary to look for complications. When giving fluids in a child whose urine output is decreased, the input should be equal to the urine and stool output plus insensible losses. Electrolytes must be carefully monitored and potassium should not be added to the fluids unless hypolkalemia is noted. Vital signs should be monitored frequently including blood pressure as hypertension may occur. Blood transfusions are required only with significant anemia (Hgb<70) or symptomatic anemia. The volume of blood given must be considered when elevating fluid status.

In approximately 50-75% of patients with HUS the renal failure requires treatment with peritoneal dialysis. The decision to use dialysis is made by a pediatric nephrologist and is based on the child's urine output, electrolyte abnormalities and fluid status. Peritoneal dialysis has potential complications such as infection and fluid leakage but is generally well tolerated in most patients. It allows the fluid and electrolyte balance to be maintained until the child begins to recover and renal function is restored.

Other treatments have been tried in HUS including fresh frozen plasma, plasmapharesis and intravenous immunoglobulin. None of them have been found to be helpful in diarrhea associated HUS. SOme of these treatments may be used in patients with other causes of HUS. Because of the association of HUS with outbreaks of E. Coli 0157:H7 infection, the medical officer of health should be notified.

The majority (65-85%) of children with HUS have full recovery from the illness. It is fatal in less than 5% of children with current management. Poor prognostic factors include elevated WBCs (>20,000), anuria for greater than 8 days, age over 3 years, atypical forms of HUS, hypertension and prominent central nervous system involvement. Chronic renal insufficiency is present in a proportion of patients after HUS. For example, GFR is decreased in 15-30% of children one year after HUS.7,8 When renal blood flow is measured, an even greater percentage of children show deficits. One study looked at children 5 years after HUS and found 23% had some sequelae such as protenuria or decreased GFR.8 Long term renal function 15 to 25 years after HUS may be less favorable than previously expected for those patients with persistent renal abnormalities.9 A small number of children eventually require renal transplantation. Unfortunately, HUS may reoccur in the new kidney.

HUS is an uncommon but significant childhood illness causing hemolytic anemia, thrombocytopenia and renal failure. HUS occurs most frequently in the context of a diarrheal illness which is a common compliant in pediatrics. As a result, it is important for all physicians who treat children to be aware of the syndrome, its key features and early management. Knowledge will enable early diagnosis and optimal treatment for those affected by HUS. The more recent increase in the discovery of coliform contamination and outbreaks of E.coli 0157:H7 in areas of Canada with usually infrequent cases of HUS serves as a additional impetus to review the current understanding of HUS and its management.

- Michelle Bailey

Thanks to Dr. Robert Bortolussi, Consultant in Infectious Diseases at the IWK Grace Hospital in Halifax NS for reviewing the draft copy of this article.